Convergent Evidence from Mouse and Human Studies Suggests the Involvement of Zinc Finger Protein 326 Gene in Antidepressant Treatment Response

abstract: ...Objectives The forced swim test (FST) is a commonly used model to predict antidepressant efficacy. Uncovering the genetic basis of the model may unravel the mechanism of antidepressant treatment. Methods FVB/NJ (FVB) and C57BL/6J (B6) were first identified as the response and non-response strains to fluoxetine (a serotonin-specific reuptake inhibitor antidepressant) treatment in the mouse FST. Simple-interval (SIM) and composite-interval (CIM) mappings were applied to map the quantitative trait loci (QTLs) of the anti-immobility effect of fluoxetine in FST (FST FLX ) in 865 male B6FVB-F2 mice. The brain mRNA expressions of the gene with the maximum QTL-linkage signal for FST FLX after the FST were compared between B6 and FVB mice and also compared between fluoxetine and saline treatment. The association of the variants in the human homologue of the mouse FST FLX -QTL gene with major depressive disorder (MDD) and antidepressant response were investigated in 1080 human subjects (MDD/control=582/498). Results One linkage signal for FST FLX -QTL was detected at an intronic SNP (rs6215396) of the mouse Zfp326 gene (maximal CIM-LOD=9.36). The Zfp326 mRNA expression in the FVB thalamus was significantly down-regulated by fluoxetine in the FST, and the higher FVB-to-B6 Zfp326 mRNA expressions in the frontal cortex, striatum and hypothalamus diminished after fluoxetine treatment. Two coding-synonymous SNPs (rs2816881 and rs10922744) in the human homologue of Zfp326 , ZNF326 , were significantly associated with the 8-week antidepressant treatment response in the MDD patients (Bonferroni-corrected p=0.0040.028). Conclusions The findings suggest the involvement of the Zfp326 and ZNF326 genes in antidepressant treatment response.

... homologue of Zfp326 , ZNF326 , were significantly associated with the 8-week antidepressant treatment response in the MDD patients (Bonferroni-corrected p=0.0040.028). Conclusions The findings suggest the involvement of the Zfp326 and ZNF326 genes in antidepressant treatment response. Introduction Antidepressants are the main biological treatment for major depressive disorder (MDD). However, there are inter-individual differences in the response to antidepressant treatments: regardless of the kind of

... consists of two single nucleotide polymorphisms (SNPs) on chromosome X and 197 SNPs on autosomal chromosomes to distinguish B6 from the FVB genetic background. In the analysis of human antidepressant response, two coding synonymous SNPs, rs2816881 C>A (Val412Val) and rs10922744 A>G (Glu505Glu), in the human ZNF326 gene were selected from the CHB (Han Chinese in Beijing) population information listed in the International HapMap Project ( http://hapmap.ncbi.nlm.nih.gov/index.html.en ). The ZNF326 gene is the human homologue of the mouse Zfp326 gene. The two SNPs tag 100% of the genetic variations in ZNF326 in the CHB population, under the marker selection criteria of no less than 10% of the minor allele frequency, greater than 0.8 in r 2 and two- and three-marker aggressive tagging with Haploview V4.1 ( http://www.broadinstitute.org/haploview/haploview-downloads ). High-throughput MALDI-TOF mass spectrometry was adopted to genotype the SNPs. In genotyping the mouse samples, one B6, FVB and two F1

... also set at 2.8 [36] . In humans, the linkage between ZNF326 rs2816881 and rs10922744 was estimated with Haploview V4.1. The difference in the haplotype frequency between groups was compared using SNPAlyze V3.5 ( http://www.dynacom.co.jp/english/ ). The significance of the comparison was determined after 100000 permutation tests. As we tested two phenotypes (major depression diagnosis and treatment response after 8 weeks of antidepressant treatment) and two SNPs, the correction factor was 4, and a

... treated with saline or fluoxetine using the Many-Whitney U test. n=810 mice for each bar. FLX: fluoxetine. FC: frontal cortex; Hip: hippocampus; HTh: hypothalamus; Amy: amygdala; NAc: nucleus accumbens; Th: thalamus; St: striatum. Association between Human ZNF326 Variations and Responses to SSRI Antidepressant Treatments There are two coding-synonymous SNPs in the human ZNF326 gene (rs2816881 (Val412Val) and rs10922744 (Glu505Glu)). They tag 100% of the overall ZNF326 genetic variations in the CHB

... episode, number of previous episodes and mean baseline HAMD scores ( Table S5 , all p>0.05). Table 2 shows the genotype and allele distributions in the study subjects. The genotype distributions of the two SNPs in the MDD and control subjects were in Hardy-Weinberg equilibrium. The genotype and allele distributions of the two ZNF326 SNPs were similar between the MDD patients and controls, but were significantly different between the responders and non-responders. The A-carrier rate of rs2816881 was

..., r 2 =1.0). The association between the two ZNF326 SNPs and antidepressant treatment response survived the corrections for multiple comparisons. 10.1371/journal.pone.0032984.t002 Table 2 Genotype and allele distribution of ZNF326 polymorphisms in the controls, and in the patients with major depressive disorder and their responses to 8-weeks antidepressant treatment. Phenotype Diagnosis 8-week treatment response SNP Genotype/allele MDD (%) Control (%) Responder (%) Non-responder (%) rs2816881 CC

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Gene: ZNF326 - zinc finger protein 326 - (NCBI)

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